The proposal intends to study critically the etiological mechanisms of human cleft lip with or without cleft palate [CL(P)] and isolated cleft palate (CP) not associated with known syndromes. Clear understanding of genetic and non-genetic basis of the etiology of these conditions is essential for estimates of recurrence risks for genetic counseling and their eventual prevention. The study proposed to gain insight into the etiology by studies of heterogeneity between groups characterized by cleft types within CL(P), mating types, risk categories, and race using a new method developed in genetic epidemiology bases on observations from the populations of Hawaii, Denmark, and Japan. The major parameters of interest represent major gene effect and multifactorial inheritance. The new method of complex segregation analysis under the mixed model (POINTER) uses the concept of pointer and enables analysis of multiple family pedigrees and powerful test of heterogeneity between groups. Among major specific aims are to answer the following questions: (1) the basis of lower recurrence risk and less sex ratio disturbance in Japanese CL(P) cases than in Caucasians despite higher population incidence in Japanese, (2) the basis of apparent differences in recurrence risks and sex ratio disturbances for CL(P) cleft types (CL, CLP, laterality), (3) the basis of increased risk of CP among individuals of Hawaiian ancestry, (4) prenatal selection as a basis of sex ratio disturbance and unexpected observation in recurrence risks in CL(P) and CP, (5) detection of differences in effects of epidemiologic factors between low risk and high risk families as classified on the basis of segregation analysis, and (6) tests of maternal effect and non-additive effect on incidences. The inquiries will be based on three different approaches: segregation analysis of pedigree, analysis of interracial crosses, and study of specific epidemiologic factors from the three sources of data.